Methods for preparing oltipraz

ABSTRACT

The invention provides improved methods of synthesizing oltipraz, which result in higher overall yield and better purity of the desired product.

RELATED APPLICATIONS

This application claims the benefit of priority to Indian provisionalpatent application serial number 1891/DEL/2015, filed Jun. 25, 2015; thecontents of which are hereby incorporated by reference.

BACKGROUND

Oltipraz, 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, depictedin Formula I, below, was originally developed as an anti-schistosomaldrug that eliminates parasitic worms. Later, it was discovered thatoltipraz is a chemopreventive agent. The drug also has other known andunknown uses in the medical field.

Various syntheses of oltipraz are known in the art. However, eachsuffers from various disadvantages, such as low overall yield, longreaction times, risk of explosion due to the use of hydride anion, andsevere environmental contamination from required large excesses of P₂S₅.

There exists a need for a fast, safe method of synthesizing oltipraz inhigh overall yield without using large excesses of P₂S₅.

SUMMARY

In certain embodiments, the invention relates to a method comprising thesteps of:

-   -   a) combining in a first container a first solvent and a first        base;    -   b) stirring the contents of the first container at a temperature        of about 0° C. for about 5 minutes;    -   c) adding to the first container, over a period of time of about        15 minutes, methyl propionate;    -   d) stirring the contents of the first container at about 0° C.        for about 15 minutes;    -   e) adding to the first container a solution of

in a second solvent, wherein the solution is added over a period of timeof about 30 minutes while warming the first container to a temperatureof about 22° C.; and the second solvent is a mixture of tetrahydrofuranand 1,4-dioxane; and

-   -   f) stirring the contents of the first container at about 22° C.        for a first period of time.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the first base is sodium pentanoate orpotassium t-butoxide.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method is a method of synthesizing

in a yield greater than 80%, greater than 81%, greater than 82%, greaterthan 83%, greater than 84%, greater than 85%, greater than 86%, greaterthan 87%, greater than 88%, greater than 89%, greater than 90%, greaterthan 91%, greater than 92%, greater than 93%, greater than 94%, greaterthan 95%, greater than 96%, greater than 97%, greater than 98%, orgreater than 99%.

In certain embodiments, the invention relates to a method ofsynthesizing oltipraz, comprising the steps of:

-   -   i) combining in a second container P₂S₅ and a first quantity of        toluene;    -   ii) heating the second container at a temperature of about 100°        C.;    -   iii) adding to the second container a solution of

in a second quantity of toluene; and

-   -   iv) heating the contents of the second container to reflux for a        second period of time, wherein no xylene is added or included at        any step.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the purity of the oltipraz produced by theclaimed methods is greater than 97%, greater than 98%, or greater than99%, as determined by gas chromatography.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the overall yield of oltipraz from

is greater than 21%, greater than 22%, greater than 23%, greater than24%, greater than 25%, greater than 26%, greater than 27%, greater than28%, greater than 29%, or greater than 30%.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the overall yield of oltipraz from

is greater than 21%, and the purity of the resulting oltipraz is greaterthan 97%, as determined by gas chromatography.

DETAILED DESCRIPTION I. Overview

In certain embodiments, the invention relates to an improved method ofsynthesizing oltipraz. In certain embodiments, the method involves Step2 or Step 3 (or both Step 2 and Step 3 in succession) as depicted inScheme 1.

In certain embodiments, the invention relates to any one of the methodsdescribed herein, wherein Step 2 does not involve sodium hydride.

In certain embodiments, the invention relates to any one of the methodsdescribed herein, wherein the yield of Step 2 is greater than 80%,greater than 81%, greater than 82%, greater than 83%, greater than 84%,greater than 85%, greater than 86%¹, greater than 87%, greater than 88%,greater than 89%, greater than 90%, greater than 91%, greater than 92%,greater than 93%, greater than 94%, greater than 95%, greater than 96%,greater than 97%, greater than 98%, or greater than 99%.

In certain embodiments, the invention relates to any one of the methodsdescribed herein, wherein the overall yield of Step 2 and Step 3 isgreater than 21%, greater than 22%, greater than 23%, greater than 24%,greater than 25%, greater than 26%, greater than 27%, greater than 28%,greater than 29%, or greater than 30%.

In certain embodiments, the invention relates to any one of the methodsdescribed herein, wherein the purity of the oltipraz produced by theclaimed methods is greater than 97%, greater than 98%, or greater than99%, as determined by gas chromatography.

In certain embodiments, the invention relates to any one of the methodsdescribed herein, wherein the overall yield of Step 2 and Step 3 isgreater than 21%, and the purity of the resulting oltipraz is greaterthan 97%, as determined by gas chromatography.

II. Exemplary Methods

It will be understood that any reaction described herein, in any of itsvariations, can be combined in sequence with one or more of the otherreactions described herein, in any of their variations, substantially inanalogy with the sequence shown in Scheme 1.

In certain embodiments, the invention relates to a method comprising thesteps of:

-   -   a) combining in a first container a first solvent and a first        base;    -   b) stirring the contents of the first container at a temperature        of about 0° C. for about 5 minutes;    -   c) adding to the first container, over a period of time of about        15 minutes, methyl propionate;    -   d) stirring the contents of the first container at about 0° C.        for about 15 minutes;    -   e) adding to the first container a solution of

in a second solvent, wherein the solution is added over a period of timeof about 30 minutes while warming the first container to a temperatureof about 22° C.; and the second solvent is a mixture of tetrahydrofuranand 1,4-dioxane; and

-   -   f) stirring the contents of the first container at about 22° C.        for a first period of time.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the first solvent is tetrahydrofuran.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the first solvent is a mixture oftetrahydrofuran and 1,4-dioxane. In certain embodiments, the inventionrelates to any of the methods described herein, wherein the firstsolvent is about a 5:1, about a 4:1, or about a 3:1 mixture by volume oftetrahydrofuran and 1,4-dioxane. In certain embodiments, the inventionrelates to any of the methods described herein, wherein the firstsolvent is about a 4:1 mixture by volume of tetrahydrofuran and1,4-dioxane.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the first base is sodium pentanoate orpotassium t-butoxide.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of the first base in thefirst solvent is from about 1.0 M to about 1.8 M. In certainembodiments, the invention relates to any of the methods describedherein, wherein the concentration of the first base in the first solventis about 1.0 M, about 1.2 M, about 1.4 M, about 1.6 M, or about 1.8 M.In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of the first base in thefirst solvent is about 1.4 M.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the mole ratio of first base to methylpropionate is from about 3:1 to about 1:1. In certain embodiments, theinvention relates to any of the methods described herein, wherein themole ratio of first base to methyl propionate is about 3:1, about 2:1,or about 1:1. In certain embodiments, the invention relates to any ofthe methods described herein, wherein the mole ratio of first base tomethyl propionate is about 1:1.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of

in the second solvent is from about 1.6 M to about 2.0 M. In certainembodiments, the invention relates to any of the methods describedherein, wherein the concentration of

in the second solvent is about 1.6 M, about 1.8 M, or about 2.0 M. Incertain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of

in the second solvent is about 1.8 M.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the mole ratio of methyl propionate to

is from about 2:1 to about 1.6:1. In certain embodiments, the inventionrelates to any of the methods described herein, wherein the mole ratioof methyl propionate to

is about 2:1, about 1.8:1, or about 1.6:1. In certain embodiments, theinvention relates to any of the methods described herein, wherein themole ratio of methyl propionate to

is about 1.8:1.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the second solvent is from about a 1.2:1 toabout a 0.8:1 mixture by volume of tetrahydrofuran and 1,4-dioxane. Incertain embodiments, the invention relates to any of the methodsdescribed herein, wherein the second solvent is about a 1.2:1, about a1:1, or about a 0.8:1 mixture by volume of tetrahydrofuran and1,4-dioxane. In certain embodiments, the invention relates to any of themethods described herein, wherein the second solvent is about a 1:1mixture by volume of tetrahydrofuran and 1,4-dioxane.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the first period of time is from about 2 h toabout 10 h. In certain embodiments, the invention relates to any of themethods described herein, wherein the first period of time is about 2 h,about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about9 h, or about 10 h. In certain embodiments, the invention relates to anyof the methods described herein, wherein the first period of time isabout 6 h.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method is a method of synthesizing

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method is a method of synthesizing

in a yield greater than 80%, greater than 81%, greater than 82%, greaterthan 83%, greater than 84%, greater than 85%, greater than 86%, greaterthan 87%, greater than 88%, greater than 89%, greater than 90%, greaterthan 91%, greater than 92%, greater than 93%, greater than 94%, greaterthan 95%, greater than 96%, greater than 97%, greater than 98%, orgreater than 99%.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method is a method of synthesizing

in a yield greater than 80%, greater than 81%, greater than 82%, greaterthan 83%, greater than 84%, greater than 85%, greater than 86%, greaterthan 87%, greater than 88%, greater than 89%, greater than 90%, greaterthan 91%, greater than 92%, greater than 93%, greater than 94%, greaterthan 95%, greater than 96%, greater than 97%, greater than 98%, orgreater than 99% without purification other than isolation.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method consists essentially of steps(a)-(f).

In certain embodiments, the invention relates to a method comprising thesteps of

-   -   i) combining in a second container P₂S and a first quantity of        toluene;    -   ii) heating the second container at a temperature of about 100°        C.;    -   iii) adding to the second container a solution of

in a second quantity of toluene; and

-   -   iv) heating the contents of the second container to reflux for a        second period of time, wherein no xylene is added or included at        any step.

In certain embodiments, the invention relates to a method comprising thesteps of:

-   -   i) combining in a second container P₂ S₅, a first quantity of        toluene, a first quantity of water, and a phase transfer        catalyst;    -   ii) heating the second container at a temperature of about 100°        C.;    -   iii) adding to the second container a solution of

in a second quantity of toluene; and

-   -   iv) heating the contents of the second container to reflux for a        second period of time,    -   wherein no xylene is added or included at any step.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of P₂S₅ in the firstquantity of toluene is from about 0.2 M to about 0.5 M. In certainembodiments, the invention relates to any of the methods describedherein, wherein the concentration of P₂S₅ in the first quantity oftoluene is about 0.2 M, about 0.25 M, about 0.3 M, about 0.35 M, about0.4 M, about 0.45 M, or about 0.5 M.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein P₂S₅ and the first quantity of toluene arecombined in the second container under an inert atmosphere. In certainembodiments, the invention relates to any of the methods describedherein, wherein P₂S₅ and the first quantity of toluene are combined inthe second container under a nitrogen atmosphere.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the volume ratio of the first quantity oftoluene to the first quantity of water is about 12:1, about 10:1, orabout 8:1. In certain embodiments, the invention relates to any of themethods described herein, wherein the volume ratio of the first quantityof toluene to the first quantity of water is about 10:1.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the phase transfer catalyst is atetraalkylammonium salt or a tetraalkylphosphonium salt. In certainembodiments, the invention relates to any of the methods describedherein, wherein the phase transfer catalyst is a tetrabutylphosphoniumsalt. In certain embodiments, the invention relates to any of themethods described herein, wherein the phase transfer catalyst istetrabutylphosphonium halide. In certain embodiments, the inventionrelates to any of the methods described herein, wherein the phasetransfer catalyst is tetrabutylphosphonium chloride.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of

in the second quantity of toluene is from about 0.2 M to about 0.4 M. Incertain embodiments, the invention relates to any of the methodsdescribed herein, wherein the concentration of

in the second quantity of toluene is about 0.2 M, about 0.3 M, or about0.4 M.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the mole ratio of P₂S₅ to

is from about 1.2:1 to about 0.6:1. In certain embodiments, theinvention relates to any of the methods described herein, wherein themole ratio of P₂S₅ to

is about 1.2:1, about 1.1:1, about 1:1, about 0.9:1, about 0.8:1, about0.7:1, or about 0.6:1.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the second period of time is from about 2 h toabout 10 h. In certain embodiments, the invention relates to any of themethods described herein, wherein the second period of time is about 2h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h,about 9 h, or about 10 h. In certain embodiments, the invention relatesto any of the methods described herein, wherein the second period oftime is about 6 h.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the

is synthesized according to steps (a)-(f), described above.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the mole ratio of

to P₂S₅ is from about 0.8:1 to about 1.8:1. In certain embodiments, theinvention relates to any of the methods described herein, wherein themole ratio of

to P₂S₅ is about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1,or about 1.8:1. In certain embodiments, the invention relates to any ofthe methods described herein, wherein the mole ratio of

to P₂S₅ is about 0.9:1. In certain embodiments, the invention relates toany of the methods described herein, wherein the mole ratio of

to P₂S₅ is about 1.4:1.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method is a method of synthesizingoltipraz.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the overall yield of oltipraz from

is greater than 21%, greater than 22%, greater than 23%, greater than24%, greater than 25%, greater than 26%, greater than 27%, greater than28%, greater than 29%, or greater than 30%.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the purity of the oltipraz produced by theclaimed methods is greater than 97%, greater than 98%, or greater than99%, as determined by gas chromatography.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the overall yield of oltipraz from

is greater than 21%, and the purity of the resulting oltipraz is greaterthan 97%, as determined by gas chromatography.

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method consists essentially of steps(i)-(iv).

In certain embodiments, the invention relates to any of the methodsdescribed herein, wherein the method consists essentially of steps(a)-(f) and steps (i)-(iv).

In certain embodiments, the invention relates to any one of the methodsdescribed herein, further comprising the steps outlined in any othermethod described herein.

In certain embodiments, the invention relates to the use of any one ofthe compounds described herein in the manufacture of a medicament.

Definitions of variables in the structures in the schemes herein arecommensurate with those of corresponding positions in the formulaedelineated herein.

In certain embodiments, the compounds described herein contain one ormore asymmetric centers and thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)-for amino acids. Optical isomers may be prepared, for example, byresolving a racemic mixture. The resolution can be carried out in thepresence of a resolving agent, by chromatography or by repeatedcrystallization or by some combination of these techniques which areknown to those skilled in the art. Further details regarding resolutionscan be found in Jacques, et al., Enantiomers. Racemates, and Resolutions(John Wiley & Sons, 1981).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent invention. Synthetic chemistry transformations useful insynthesizing the compounds described herein are known in the art andinclude, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed.,John Wiley and Sons (1991): L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Exemplification

The present invention is further illustrated by the following Examplewhich should not be construed as limiting in any way. The Examples anddiscoveries described herein are representative. As such, the studiesand results described in the Examples section herein may be used as aguideline.

Example 1 Synthesis of pyrazine-2-carboxylic acid methyl ester ST-601(Step 1)

Input:

Pyrazinoic acid (OT-1) (1758 g, SM)

Sulfuric Acid (69.5 g) MeOH (8.8 L) Procedure:

-   -   Charged MeOH (8.8 L) and OT-1 (1758 g) at RT.    -   Charged H₂SO₄ (69.5 g) in one portion (21-22° C. exotherm).        Heated to (60-65° C.) and stirred at 55-65° C. for 19 hours.

19 h, 96.0% OT-2 and 4.0% OT-1 by HPLC

-   -   Reaction was cooled to 15/30° C. No precipitate formed.    -   NaHCO₃ (180 g) was charged in lots. The solution bubbled        slightly and quickly went from yellow to pink. The mixture was        stirred for 5 min at 15/30° C.    -   The mixture was then concentrated to 1.5-2.5 vol at <30° C.    -   Charged NaCl (0.700 g) in water (2.5 vol). Upon stirring,        solution became clear.    -   Stirred for 15 min at 15/30° C. After stirring, the aqueous        layer became slightly cloudy. The solids were filtered off and        the layers were separated.    -   The aqueous layer was extracted with DCM (3×2 vol.). TLC        indicated that extraction was complete after 3rd extraction.    -   Organic layers were dried over anhydrous Na₂SO₄ (0.4 g/g SM).    -   Concentrated to 1.5-2.5 vol under vacuum at <30° C. Some        precipitate formed.    -   Charged heptanes (8 vol) over a minimum of 30 min. Pale white        slurry. Let stir overnight.    -   Stirred at −5/−15° C. for a minimum of 1 hr. Solids were        filtered off and rinsed with cold heptanes    -   (2× l vol.) Pulled solids dry on filter for 10 min. Dried in        vacuum oven at <30° C. to constant mass. Dried over weekend.        Solids went from pale white to light brown.    -   Color changed, but no degradation was observed.

Output Material: ST-601 Lot No.: 2463-24-1

Appearance: light Brown Solids

Yield: 1721 g (91.0%)

HPLC purity: 98.9%¹H NMR—Conforms to structure

Example 2—Synthesis of methyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate,ST-602 (Step 2)

Input: ST-601 (1000 g); Lot #2463-24-1

Methyl propionate (64 g+893 g); Lot #11-2713-56+11-2713-57+R11-1913-101NaH in mineral oil, 60 wt. %, (579 g)Toluene (10 vol)

Procedure:

-   -   Charged ST-601 (1 kg), NaH, 60 wt. % (579 g) and toluene (10        vol) and stirred at 15/25° C. No reaction (no gas evolution,        exotherm or appearance change).    -   Charged methyl propionate (64 g). No immediate reaction (no gas        evolution, exotherm or appearance change) at 15/25° C.    -   Charged MeOH (85 g) at 15/25° C. Immediately started to react        (gas evolution, exotherm). Heated to 30/40° C.    -   Charged methyl propionate (893 g) at 30/40° C. over 5 h. The        reaction was slower in the beginning, but became faster (more        exotherm and gas evolution) after 1-2 h when ˜0.3 eq of methyl        propionate was charged. Stirred at 30/40° C. for 88 h.        64 h, 30/35° C., brown slurry, practically no gas evolution        observed, IPC HPLC1: 74.4%+14.1%=88.5% of ST-602 at 4.81 min and        5.62 min; 1.2% of ST-601 at 1.97 min; 5.8% of “Int” at 3.21 min.        72 h, 35° C., IPC HPLC2: 47.8%+42.9%-90.7% of ST-602; 0.9% of        ST-601; 4.3% of “Int” 88 h, 38° C., IPC HPLC3: 60.3%+32.6%=92.9%        of ST-602; 0.64% of ST-601; 1.8% of “t”    -   Reaction was cooled to 15/20° C.    -   Charged AcOH (2.5 eq) over a minimum of 1 hr. Exothermic.        Slightly thick, brown suspension.    -   Charged 10% NaCl solution (8 vol) over a minimum of 1 h at        15/30° C. Slight exotherm. Brown, biphasic solution. Let stir at        15/30° C. for a minimum of 30 min to dissolve all solids.    -   The phases were separated. Both the aqueous and the organic        phases were brown.    -   The organic phase was washed with a 10% NaCl solution (5 vol).    -   The organic phase was washed with NaHCO₃ (0.1 g/g SM) in 10% aq.        NaCl solution (5 vol.)    -   The organic phase was dried over anhydrous sodium sulfate (0.2        g/g SM) for a minimum of 2 hrs.    -   Solids were filtered off and rinsed with Toluene (1×1 vol)    -   Concentrated to 3-4 vol at <50° C.

Isolated Material: ST-602 Lot No.: 2463-52-2

Appearance: light brown liquidYield: Assumed 100% (1406 g net directly used in next step)

HPLC: 94.3% of ST-602 Example 3—Synthesis of crude4-methyl-5-(pyrazin-2-L)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Input:

ST-602 (from 1 kg of ST-601 (SM), 1 eq); Lot #2463-52-2P₂S₅ (1931 g); Lot #11-1513-52Toluene (15 vol)

Observations:

-   -   Charged ST-602 in toluene (˜3.5 L; 3-4 vol) to P₂S₅ (1931 g) in        toluene (10 L; 10 vol). Rinsed with toluene (1 L; 1 vol). No        exothermic effect, yellow slurry.    -   Reaction over after 36 h at 95-97° C.

36 h, −95° C., IPC HPLC lot #2463-54-1: 95.2% of ST-617 at 6.85 min and4.8% of ST-602 at 4.79 min

-   -   Work-up (after 36 h at ˜95° C.); Cooled to RT over 20 mins    -   Charged the slurry via a transfer line to a mixture of Na₂CO₃        (2686 g; 3.5 eq), water (15 L; 15 vol) and THF (5 L; 5 vol) at        15/30° C. over a minimum of 1 h—weak exothermic effect and no        gas evolution observed.    -   The resulting mixture was slowly transferred back to the parent        flask—some gas evolution observed. Minor insolubles were        observed.    -   The resulting mixture was stirred at RT for 65 h (shouldn't need        more than 12 h) to complete gas evolution/quench of the reaction        mixture    -   The resulting mixture was passed through a 0.5″ celite bed to        remove fine insolubles.    -   The organic layer was separated, dried with Na₂SO₄ (200 g; 0.2        g/g SM) and concentrated under reduced pressure at <50° C. to        2-4 L (2-4 vol) residue volume (3 L actual)—product precipitates        during concentration.    -   The resulting slurry was diluted with MeOH (1.5 L; 1.5 vol) and        stirred at RT for 2 h.    -   The solids were collected by filtration, rinsed with MeOH (2×500        mL; 2×0.5 vol) followed by heptane (1 L+0.5 L; 1+0.5 vol).    -   Dried in air to yield constant weight.        Isolated Material: ST-603 (crude ST-617)

Lot No.: 2463-55-1

Appearance: red solid powder (crystals not uniform)

Yield: 223 g (14%)

HPLC: 99% by R&D method

Example 4—Purification of Crude ST-617 (Step 4) Input: ST-603 (220 g);Lot #2463-55-1 DMSO (2.2 L+220 mL)

Water (330 mL; 1.5 vol)

Observations:

-   -   Added ST-603 into DMSO (2.2 L) and heated to 65° C.    -   Clear solution in DMSO at ˜65° C. Heated further to ˜80° C. and        hot filtered at ˜80° C.    -   Hot filtration was easy to perform (no fast precipitation of        product).    -   Diluted with water at 70/85° C. to initiate product        precipitation.    -   The mixture was chilled/stirred at RT for 1 hour    -   Collected the solids by filtration, rinsed with 5:1 DMSO/water        (2×1.5 vol) and MeOH (2×1.5 vol) sequentially.    -   Re-slurried in MeOH (8 mL) at RT for 70 h (shouldn't need more        than 4-6 hours) to help wash out DMSO and collected by        filtration.    -   Finally rinsed with MeOH (2×1.5 vol) and dried in a vacuum oven        at 30/40° C. to yield constant weight.

Isolated Material: ST-617 Lot No.: 2463-57-1

Appearance: brown-red solid

Yield: 191 g (87%)

HPLC: 99.5% by R&D method¹H NMR (CDCl₃): conforms to structure (clean) with residual DMSO (0.3wt. %)

Example 5—Synthesis of pyrazine-2-carboxylic acid methyl ester, ST-601(Step 1)

Aim: Carry out 170-g-scale Step 1

Procedure:

-   1. Added 900 mL of MeOH and 175 g of OT-1 into a 2-neck 2-liter RBF    at 22° C. on a heating mantle.-   2. Added 7 grams of concentrated sulfuric acid in one portion into    the RBF.-   3. Heated to 65° C. and stirred for 24 hours.-   4. TLC at 24 hrs indicates little to no OT-1 (Rf 0.1 in 95:5    Hexane:EtOAc) left and new spot which is the same as authentic    ST-601 at Rf 0.7-   5. Reaction was cooled to RT (22° C.). No precipitate formed.-   6. 75 g of Sodium Bicarbonate was added. Slight gas evolution and    colour goes from yellow to pink.-   7. The mixture was stirred for 10 min at 22° C.-   8. The mixture was transferred to a 1-neck RBF and set on a rotovap.-   9. The mixture was then concentrated to ˜200 mL at <30° C.-   10. Added a prepared solution of 70 g of NaCl in 400 mL of water.    Upon stirring, the solution became clear.-   11 Stirred for 10 min at 22° C. After stirring, the solution became    slightly cloudy. The solids were filtered on a Buchner filter.-   12. The aqueous layer was extracted three times with 200 ml of    dichloromethane each time-   13. The dichloromethane layers were combined and 50 g of anhydrous    sodium sulfate was added to the solution. Stirred for 5 min and    filtered on Buchner.-   14. The solution was concentrated to ˜50 mL on a Rotovap under    vacuum at <30° C. Some precipitate was visible but very fine.-   15. Added 700 mL of mixed heptanes over ˜45 min. A pale white slurry    formed which was stirred gently overnight.-   16. Cooled the RBF to −15° C. (dry ice batch) and stirred for 2    hours.-   17. Thicker solids formed which were filtered on a Buchner.-   18. The residue was rinsed with refrigerated mixed heptanes two    times with 200 mL each.-   19. Pulled the solids dry on the Buchner for 15 min. Transferred to    tared dish.-   20. Set to dry in vacuum oven at ≤30° C. overnight.-   21. Color of powder is pale brown.-   22. GC (in lab) shows 98.4% purity versus authentic-   23. Weight of powder is 168 g (89% yield)-   24. Labelled as ST-601-001

Example 6—Synthesis of methyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate,ST-602 (Step 2)

Aim; Establish baseline for Step 2 using NaH as the base.

Procedure

-   1. Add 2.5 g (0.0181 mole) of ST-601, 1.4 g of 60% NaH in oil and 25    mL of toluene into a 100-mL 2-neck RBF at 22° C. and stir for 30 min    to thoroughly strip the oil off the NaH. No gas evolution or    temperature change was observed.-   2. Added 250 mg of methyl propionate into the flask with no exotherm    or gas evolution observed.-   3. Added 2.5 mL of methanol.-   4. Immediately started to react with gas evolution and exotherm.-   5. Heated to 40° C.-   6. Added 2.3 g of methyl propionate dropwise from addition funnel at    1 mL/20 min.-   7. The reaction became more vigorous after 30 min of addition.-   8. Stirred at 40° C.-   9. Monitored by HPLC (GeoChem Method ST1). After 24 hrs at 40° C.    the reaction is a brown slurry and no gas was being evolved. HPLC    showed two peaks (same as for authentic ST-602) totaling 82.4% and    2.1% of ST-601 and with an intermediate peak of 15.2% (all area %    peaks)-   10. After 72 h at 40° C. the reaction is a brown slurry with no gas    being evolved. HPLC showed two peaks (same as for authentic ST-602)    totaling 96.0% and 0.5% of ST-601 with an intermediate peak of 1%    (all area % peaks)-   11. The reaction was cooled to 22° C. (RT) and 3 mL of glacial    acetic acid was added slowly. (some slow gas evolution). Then added    in 100 mL of 10% aq. NaCl solution with stirring. The organic layer    was separated and washed with 100 mL of 10% aq. NaCl+10% NaHCO₃ and    dried over 10 g of sodium sulfate anhydrous. The slurry was filtered    on a Buchner and the reside washed 1× with 20 mL of toluene.-   12. Concentrated on a rotovap at <50° C. to ˜5 mL.-   13. The above reference standard reaction product will be considered    the crude standard required for use of un-isolated ST-602 in the    next cyclization step.-   14. The orange-brown solution will be used as is in Step 3    cyclization yield verification step.-   15. Labeled as ST-602-002

Example 7—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim: Replace base in Step 2 with t-butoxide

Procedure

-   1. Added 4.1 g (0.0362 mole) of potassium t-butoxide powder and 25    mL of dry THF into a 100-mL 2-neck RBF at 0° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turns yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF and    added into the reaction over 30 minutes while allowing the reaction    to come to RT(˜½ hr). No gas evolution or exotherm.-   5. Stirred at reflux for 24 hours-   6. Monitored by HPLC (Method ST). After 24 hrs at reflux the    reaction is a brown slurry-   7. HPLC showed two peaks (same as for authentic ST-602) totaling    32.6% and 39.7% of ST-601 and with an intermediate peak of 18% (all    area % peaks)-   8. After 72 hrs at reflux the reaction was a dark brown slurry.-   9. HPLC showed two peaks (same as for authentic ST-602) totaling    36.8% and 38.2% of ST-601 with an intermediate peak of 12.5% (all    area % peaks)-   10. Concentrated on a rotovap at ˜50° C.-   11. The 2.5 dark brown solution will be used as is in Step 3    cyclization yield verification step.-   12. Labeled as ST-602-003

Example 8—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate ST-602 (Step 2)

Aim: Replace base in Step 2 with sodium pentanoate

Procedure

-   1. Add 4.5 g (0.0362 mole) of sodium pentanoate (Mwt 124) powder and    25 mL of dry THF into a 100-mL 2-neck RBF at 0° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. Add 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF    and added into the reaction over 30 minutes while allowing the    reaction to come to RT (˜½ hr). No gas evolution or exotherm.-   5. Stirred at reflux for 24 hours-   6. Monitored by HPLC (Method ST1). After 24 hrs at reflux the    reaction is a yellow-brown slurry-   7. HPLC showed two peaks (same as for authentic ST-602) totaling    18.3% and 20.4% of ST-601 and with an intermediate peak of 39.9%    (all area % peaks)-   8. After 72 hrs at reflux the reaction is a dark brown slurry.-   10. HPLC showed two peaks (same as for authentic ST-602) totaling    26.9% and 21.7% of ST-601 with an intermediate peak of 35.3% (all    area % peaks)-   11. Concentrated on a rotovap at ≤50° C. to ˜5 mL-   12. The dark brown solution will be used as is in Step 3 cyclization    yield verification step.-   13. Labeled as ST-602-004

Example 9—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-61?(Step 3)

Aim: Establish baseline for Step 3

Procedure

-   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL of Toluene into a    100-mL 2-neck RBF under nitrogen-   2. Yellow slurry but easily stirable.-   3. Added crude ST-602-002 solution (˜5 mL). Yellow-brown slurry.-   4. Started stirring and heated to 50° C., color changed to reddish    brown in 10 min. Slow H₂S gas evolution was observed which is passed    through a caustic bubbler and no H₂S was exited.-   5. Continued heating up to 95° C. and let stir for 36 hours.-   6. A sample was taken for HPLC (method ST-1). No starting material    present. Product ST-603 was present but also many other small peaks.    Area % of ST-603 is 88.8% against authentic sample with 5.4% ST-602-   7. The reaction was cooled to 22° C. (RT)-   8. In a 100-mL beaker was prepared a quenching mixture of 7 g of    solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.-   9. To the above beaker was slowly added (over 10 min) the content of    the reaction flask. Weak exotherm was observed but no H₂S gas was    smelt at all.-   10. The resulting mixture was stirred over 12 hours to complete    quench of the reaction (in a very high vent hood attached to a    scrubber for safety). Some insolubles were visible at the end of the    12 hours.-   11. The reaction slurry was passed through a 1″-celite bed to remove    fine insolubles.-   12. The organic layer was separated (both are colored red), dried    over 2 g anhydrous sodium sulfate, and concentrated on a rotovap at    <50° C. to 20 mL volume. Solid ppt is observed during concentration.-   13. The resulting slurry was diluted with 20 mL of methanol and    stirred at RT for 2 h.-   14. The solids were collected by filtration, rinsed 2× with 20 mL of    refrigerated cold methanol followed by 20 mL of cold heptane.-   15. Dried in vacuum oven to constant weight.-   16. Weight of powder is 348 mg (˜12% yield)-   17. HPLC showed 98.2% product against authentic sample.-   18. Sent 20 mg to IPAC for ¹H NMR.-   19. Labelled as ST-603-005

Example 10 Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 to study cyclization of crude mixture frompotassium t-butoxide condensation.

Procedure

-   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL of Toluene into a    100-mL 2-neck RBF under nitrogen.-   2. Yellow slurry.-   3. Added crude ST-602-003 solution (˜5 mL). Brown slurry (difficult    to stir)-   4. Started stirring and heated to 50° C. No color change. Slow H₂S    gas evolution is observed which is passed through a caustic bubbler    and no H₂S is exited.-   5. Continued heating up to 95° C. and let stir for 36 hours.-   6. A sample was taken for HPLC (method ST-1): 601 (25%), and 602    (18%), and 8% ST-603 was present, but also many other small peaks.-   7. The reaction was cooled to 22° C. (RT)-   8. In a 100-mL beaker was prepared a quenching mixture of 7 g of    solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.-   9. To the above beaker was slowly added (over 10 min) the content of    the reaction flask. Weak exotherm was observed but strong smell of    H₂S gas.-   10. The resulting mixture was stirred over 12 hours to completely    quench the reaction (in a very high vent hood attached to a scrubber    for safety). Lots of insolubles are visible at the end of the 12    hours.-   11. The reaction slurry was passed through a 1″ celite bed to remove    fine insolubles. Very difficult filtration, so left for over 12    hours.-   12. After finally getting two phase filtrate, the organic layer was    separated (both are colored brown), dried over 2 g anhydrous sodium    sulfate and concentrated on a rotovap at <50° C. to 20 mL volume. No    solid ppt was observed during concentration.-   13. The resulting solution was diluted with 20 mL of methanol and    stirred at RT for 2 h.-   14. No solids were observed, so added 20 mL of cold heptane. Still    no solids. Left in refrigerator for 24 hrs but still no solids    formed.

Example 11—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 to study cyclization of crude mixture from sodiumpentanoate condensation.

Procedure

-   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL of Toluene into a    100-mL 2-neck RBF under nitrogen.-   2. Yellow slurry.-   3. Added crude ST-602-003 solution (˜5 mL). Brown stirrable slurry-   4. Started stirring and heated to 50° C. Slight color change to    reddish hue. Slow H₂S gas evolution is observed which is passed    through a caustic bubbler and no H₂S is exited.-   5. Continued heating up to 95° C. and let stir for 36 hours.-   6. A sample was taken for HPLC (method ST-1): 601 (10%) and 602    (17%) and 43% ST-603 was present, but also many other small peaks.-   7. The reaction was cooled to 22° C. (RT)-   8. In a 100-mL beaker was prepared a quenching mixture of 7 g of    solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.-   9. To the above beaker was slowly added (over 10 min) the content of    the reaction flask. Weak exotherm was observed and some smell of H₂S    gas.-   10. The resulting mixture was stirred over 12 hours to completely    quench the reaction (in a very high vent hood attached to a scrubber    for safety). Some insolubles are visible at the end of the 12 hours.-   11. The reaction slurry was passed through a 1″ celite bed to remove    fine insolubles. Difficult filtration over 6 hour period.-   12. Two phase filtrate both red/brown in color—the organic layer was    separated, dried over 2 g anhydrous sodium sulfate and concentrated    on a rotovap at <50° C. to 20 mL volume. No solid ppt was observed    during concentration.-   13. The resulting solution was diluted with 20 mL of methanol and    stirred at RT for 2 h.-   14. No solids were observed, so added 20 mL of cold heptane. Still    no solids. Left in refrigerator for 24 hrs, but still no solids    formed.

Example 12—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim. Replace base in Step 2 with excess sodium pentanoate

Procedure

-   1. Add 9 g (0.0724 mole) of sodium pentanoate (MWt 124) powder and    25 mL of dry THF into a 100-mL 2-neck RBF at 0° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. Add 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF    and added into the reaction over 30 minutes while allowing the    reaction to come to RT (˜½, hr). No gas evolution or exotherm.-   5. Stirred at reflux for 24 hours-   6. Monitored by HPLC (Method ST1). After 24 hrs at reflux the    reaction is a yellow-brown slurry-   7. HPLC showed two peaks for ST-602 totaling 72.4%, and 12.1% of    ST-601 and with an intermediate peak of 8.3% (all area % peaks) and    many small peaks that were not present in baseline experiment-   8. After 72 hrs at reflux the reaction is a dark brown slurry.-   9. HPLC shows two peaks for ST-602 totaling 77.5%, and 9.2% of    ST-601 with an intermediate peak of 4.1% (all area % peaks) and same    smaller peaks.-   10. Concentrated on a rotovap at <50° C. to ˜5 mL-   11. The dark brown solution may be used as is in P₂S₅ cyclization    step.-   12. Labeled as ST-602-008

Example 13—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 to study cyclization of crude mixture from sodiumpentanoate condensation.

Procedure

-   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL of Toluene into a    100-mL 2-neck RBF under nitrogen.-   2. Thick, yellow slurry.-   3. Added crude ST-602-003 solution (˜5 mL). Brown, stirrable slurry-   4. Started stirring and heated to 50° C. Slight color change to    red-brown. Slow H₂S gas evolution was observed, which was passed    through a caustic bubbler and no H₂S was exited.-   5. Continued heating up to 95° C. and let stir for 36 hours.-   6. A sample was taken for HPLC (method ST-1): 601 (10%) and 602    (17%) and 43% ST-603 was present, but also many other small peaks.-   7. The reaction was cooled to 22° C. (RT)-   8. In a 100-mL beaker was prepared a quenching mixture of 7 g of    solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.-   9. To the above beaker was slowly added (over 10 min) the content of    the reaction flask. Weak exotherm was observed and some smell of H₂S    gas.-   10. The resulting mixture was stirred over 12 hours to completely    quench the reaction (in a very high vent hood attached to a scrubber    for safety). Some insolubles were visible at the end of the 12    hours.-   11. The reaction slurry was passed through a 1″ celite bed to remove    fine insolubles. Difficult filtration over 6 hour period.-   12. Two phase filtrate both red/brown in color—the organic layer was    separated, dried over 2 g anhydrous sodium sulfate, and concentrated    on a rotovap at <50° C. to 20 mL volume. No solid ppt was observed    during concentration.-   13. The resulting solution was diluted with 20 mL of methanol and    stirred at RT for 2 h.-   14. No solids were observed, so added 20 mL of cold heptane. Still    no solids. Left in refrigerator for 24 hrs and some solids were    visible.-   15. Reduced the volume to 5 mL on a rotovap and added fresh cold 20    mL heptane. Left in refrigerator overnight.-   16. The solids were collected by filtration, rinsed 2× with 20 mL of    refrigerated cold methanol followed by 20 mL of cold heptane.-   18. Dried in vacuum oven to constant weight.-   19. Weight of Powder is 139 mg (˜4.8% yield)-   20. HPLC shows 94.8% ST-617 product against authentic sample.-   21. Labelled as ST-603-009

Example 14—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim; Replace base in Step 2 with 2× sodium pentanoate

Procedure

-   1. Add 4.5 g (0.0362 mole) of sodium pentanoate (MWt 124) powder and    25 mL of dry THF into a 100-mL 2-neck RBF at 0° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF and    added into the reaction over 30 minutes while allowing the reaction    to come to RT (˜½ hr). No gas evolution or exotherm.-   5. Stirred for 24 hours at RT-   6. TLC shows product (ST-602) spot (Rf 0.4) begins forming after 2    hrs at RT and an intermediate spot (Rf 0.2) and spot for ST-601 is    still also visible. Second 2 hr TLC shows more product spot but    still shows both intermediate and ST-601 spots. After 6 hrs ST-602    spot and only trace of intermediate and ST-601. Stirred overnight.    After 16 hrs no change from 6 hr TLC.-   7. 20 mL of distilled water and 20 mL of saturated sodium chloride    solution were added to the reaction solution and stirred for 30    minutes.-   8. The reaction solution was concentrated to a volume of 40 mL and    then extracted with 2×25 mL of toluene.-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered-   10. The filtrate was rotovaped to give 1.9 g crude ST-602 as a dark    brown viscous oil-   11. Labeled as ST-602-010

Example 15—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-ylpropanoate, ST-602 (Step 2)

Aim; Replace base in Step 2 with 2× sodium pentanoate and varytemperature

Procedure

-   1. Add 4.5 g (0.0362 mole) of sodium pentanoate (Mwt 124) powder and    25 mL of dry THF into a 100-mL 2-neck RBF at 0° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. Add 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF    and added into the reaction over 30 minutes while allowing the    reaction to come to RT(˜½ hr). No gas evolution or exotherm.-   5. Warmed to 40° C.-   6. Monitored on TLC every 2 hours-   7. TLC showed product (ST-602) spot (Rf 0.4) after 2 hrs at RT with    almost no ST-601 but a long streaking along the plate.-   8. Continued at 40° C. to complete the experiment for 6 hrs-   9. 20 mL of distilled water and 20 mL of saturated sodium chloride    solution were added to the reaction solution and stirred for 30    minutes.-   10. The reaction solution was concentrated to a volume of 45 mL and    then extracted with 2×25 mL of toluene-   11. The resultant extract was almost black in color and had    suspended solids and was very tarry in form-   15. Labeled as ST-602-011 but kept for discard.

Example 16—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-ylpropanoate, ST-602 (Step 2)

Aim; Replace base in Step 2 with 2× sodium pentanoate, use warmertemperature for formation of anion, and stop reaction after 6 h

Procedure

-   1. Add 4.5 g (0.0362 mole) of sodium pentanoate (MWt 124) powder and    25 mL of dry THF into a 100-mL 2-neck RBF at 10° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (MWt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 10° C.-   4. Add 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF    and added into the reaction over 30 minutes while allowing the    reaction to come to RT (˜½ hr). No gas evolution or exotherm.-   5. Stirred at RT for 6 hours. Monitor on TLC every 2 hours-   6. TLC showed product (ST-602) spot (Rf 0.4) begins forming after 2    hrs at RT and an intermediate spot (Rf 0.2) and spot for ST-601 is    still also visible. Second 2 hr TLC showed more product spot but    still showed both intermediate and ST-601 spots. After 6 hrs ST-602    spot and only trace of intermediate and ST-601 is visible.-   7. 20 mL of distilled water and 20 mL of saturated sodium chloride    solution were added to the reaction solution and stirred for 30    minutes-   8. The reaction solution was concentrated to a volume of 45 mL and    then extracted with 2×25 mL of toluene.-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered.-   10. The filtrate was rotovaped to give 2.7 g crude ST-602 as a brown    oil with no tarry nature.-   11. Labeled as ST-602-012 and carried forward for cyclization    experiment

Example 17—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim; Carry out Step 3 using the solvent system described in U.S. Pat.No. 7,288,652 to establish baseline

Procedure

-   1. Added 5.65 g (0.025 mole) of P₂S₅ and 25 mL Toluene+25 mL mixed    xylenes into a 100-mL 2-neck RBF under nitrogen.-   2. Yellow slurry but easily stirrable.-   3. Heated to 120° C. while stirring-   4. Added crude ST-602-012 solution HO mL in toluene). Yellow-brown    slurry.-   5. Started stirring and heated to reflux (˜140° C.). Color changes    to reddish brown in 5 mins. Slow H₂S gas evolution was observed,    which was passed through a caustic bubbler and no H₂S is exited.-   6. Continued reflux for 6 hours.-   7. A sample was taken for HPLC (method ST-1): no starting material    present, and product ST-603 was present but also some other small    peaks.-   8. The reaction was cooled to 25° C. (RT)-   9. In a 100-mL beaker was prepared a quenching mixture of 7 g of    solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.-   10. To the above beaker was slowly added (over 10 min) the content    of the reaction flask. Weak exotherm was observed but no H₂S gas    smell at all.-   11. The resulting mixture was stirred over 3 hours to complete    quench of the reaction (in a very high vent hood attached to a    scrubber for safety). Very few insolubles are visible at the end of    the 3 hours.-   12. The reaction slurry was passed through a 1″ celite bed to remove    the fine insolubles.-   13. The organic layer was separated (both are colored red), dried    over 2 g anhydrous sodium sulfate, and concentrated on a rotovap at    <50° C. to 20 mL volume.-   14. The resulting slurry was diluted with 20 mL of methanol and    stirred at RT for 2 h resulting in solids-   15. The solids were collected by filtration, rinsed 2× with 20 mL of    refrigerated cold methanol followed by 20 mL of cold heptane.-   16. Dried in vacuum oven to constant weight.-   17. Weight of crude ST-603 crystalline powder is 609 mg (˜21% yield)-   18. Labelled as ST-603-013.

Example 18—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl propanoate, ST-602 (Step 2)

Aim: Replace base in Step 2 with 2× sodium pentanoate, use 15%1,4-dioxane in THF as solvent system for reaction

Procedure

-   1. Added 4.5 g (0.0362 mole) of sodium pentanoate (MWt 124) powder    and 25 mL of dry THF into a 100-mL 2-neck RBF at 0° C. Stirred for 5    minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turns yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 5 mL of THF+5 mL    of 1,4-Dioxane and added into the reaction over 30 minutes while    allowing the reaction to come to RT (˜½ hr). No gas evolution or    exotherm.-   5. Stirred at RT for 6 hours. Monitored by TLC every 2 hours.-   6. TLC shows product (ST-602) spot (Rf 0.4) begins forming after 2    hrs at RT and an intermediate spot (Rf 0.2) and spot for ST-601 is    still also visible. Second 2 hr TLC shows more product spot but    still shows both intermediate and ST-601 spots. After 6 hrs, ST-602    spot and only trace of intermediate and ST-601 spots were visible.-   7. 30 mL of distilled water and 30 mL of saturated sodium chloride    solution were added to the reaction solution (extra aqueous layer    added due to more polar 1,4-dioxane and stirred for 30 minutes.-   8. The reaction solution was concentrated to a volume of 60 mL and    then extracted with 2×25 mL of toluene.-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered.-   10. The filtrate was rotovaped to give 3.1 g crude ST-602 as a brown    oil with no tarry nature-   11. Labeled as ST-602-014 (GC shows 84% ST-002 peak)

Example 19—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim: Replace base in Step 2 with 2× sodium pentanoate, use 1,4-dioxaneas solvent system for reaction

Procedure

-   1. Added 4.5 g (0.0362 mole) of sodium pentanoate (Mwt 124) powder    and 25 mL of dry 1,4-dioxane into a 100-mL 2-neck RBF at 0° C.    Stirred for 5 minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of    1,4-Dioxane and added into the reaction over 30 minutes while    allowing the reaction to come to RT (˜½ hr). No gas evolution or    exotherm.-   5. Stirred at RT for 6 hours. Monitored by TLC every 2 hours.-   6. TLC showed product (ST-602) spot (Rf 0.4) begins forming after 2    hrs at RT but multiple new trailing spots also present. After 6 hrs,    ST-602 spot, no ST-601 but lots of multiple smaller spots were    visible.-   7. 50 mL of distilled water and 50 mL of saturated sodium chloride    solution were added to the reaction solution (extra aqueous layer    added due to more polar 1,4-dioxane) and stirred for 30 minutes.-   8. The reaction solution was concentrated to a volume of 100 mL    (using a high vacuum on the rotovap) and then extracted with 2×25 mL    of toluene-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered-   10. The filtrate was rotovaped to give 1.8 g crude ST-602 as a brown    oil with some tarry nature-   11. Labeled as ST-602-015 (GC shows 68% ST-002 peak)

Example 20—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim: Replace base in Step 2 with 2× sodium pentanoate, use 1,4-dioxaneas solvent system for reaction, complete reaction at 0° C.

Procedure

-   1. Added 4.5 g (0.0362 mole) of sodium pentanoate (MWt 124) powder    and 25 mL of dry 1,4-dioxane into a 100-mL 2-neck RBF at 0° C.    Stirred for 5 minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned yellow.-   3. Stirred for an additional 15 minutes at 0° C.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of    1,4-Dioxane and added into the reaction over 30 minutes. No gas    evolution or exotherm.-   5. Stirred at 0° C. for 6 hours. Monitored by TLC every 2 hours.-   6. TLC shows a small amount of product (ST-602) spot (Rf 0.4) began    forming after 2 hrs at RT. Intermediate spot was visible and large    ST-601 spot. After 4 hrs, no real change in TLC. Skipped the 6 hr    TLC and stirred overnight (12 hrs) at 0° C. TLC now shows more    ST-602 but still ˜20% ST-601 was visible. Allowed the reaction to    warm up to 10° C. and stirred for 2 hrs more. All the ST-601 was    gone, many trialing spots were visible so reaction was taken for    workup.-   7. 50 mL of distilled water and 50 mL of saturated sodium chloride    solution were added to the reaction solution (extra aqueous layer    added due to more polar 1,4-dioxane) and stirred for 30 minutes-   8. The reaction solution was concentrated to a volume of 110 mL    (using a high vacuum on the rotovap) and then extracted with 2×25 mL    of toluene.-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered-   10. The filtrate was rotovaped to give 2.0 g crude ST-602 as a brown    oil with almost no tarry nature.-   11. Labeled as ST-602-016 (GC showed 71% ST-002 peak)

Example 21—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim: Replace base in Step 2 with 2× sodium pentanoate, use 30%1,4-dioxane in THF as solvent system for reaction

Procedure

-   1. Added 4.5 g (0.0362 mole) of sodium pentanoate (MWt 124) powder    and 20 mL of dry THF+5 mL 1,4-dioxane into a 100-mL 2-neck RBF at    0° C. Stirred for 5 minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned pale    yellow.-   3. Stirred for an additional 15 minutes at 0° C. No color change.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 5 mL of THF+5 mL    of 1,4-Dioxane and added into the reaction over 30 minutes while    allowing the reaction to come to RT (˜½ hr). No gas evolution or    exotherm.-   5. Stirred at RT for 6 hours. Monitored by TLC every 2 hours.-   6. TLC showed ˜60% product (ST-602) spot (Rf 0.4) began forming    after 2 hrs at RT and an intermediate spot (Rf 0.2) and <10% spot    for ST-601 was still also visible. Second 2 hr TLC showed more    product spot and intermediate spot but no ST-601 spot. After 6 hrs    ST-602 spot only and some trailing spots visible.-   7. 30 mL of distilled water and 30 mL of saturated sodium chloride    solution were added to the reaction solution and stirred for 30    minutes-   8. The reaction solution was concentrated to a volume of 65 mL    (vacuum of 14 mmHg was adequate on rotovap) and then extracted with    2×30 mL of toluene-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered.-   10. The filtrate was rotovaped to give 3.3 g crude ST-602 (MWt=194)    as a brown oil with no tarry nature-   11. Labeled as ST-602-017 to be carried forward for cyclization    experiment

Example 22—Alternative synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate ST-602 (Step 2)

Aim: Replace base in Step 2 with 2× potassium t-butoxide, use 30%1,4-dioxane in THF as solvent system for reaction

Procedure

-   1. Added 4.1 g (0.0362 mole) of potassium t-butoxide powder    (MWt 112) powder and 20 mL of dry THF+5 mL 1,4-dioxane into a 100-mL    2-neck RBF at 0° C. Stirred for 5 minutes-   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into the    flask using a dropping funnel over 15 minutes. Color turned pale    yellow.-   3. Stirred for an additional 15 minutes at 0° C. No color change.-   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 5 mL of THF+5 mL    of 1,4-Dioxane and added into the reaction over 30 minutes while    allowing the reaction to come to RT (˜½ hr). No gas evolution or    exotherm.-   5. Stirred at RT for 6 hours. Monitor on TLC every 2 hours.-   6. Very similar TLC profile as previous Example. TLC showed ˜60%    product (ST-602) spot (Rf 0.4) began forming after 2 hrs at RT and    an Intermediate spot (Rf 0.2) and <10% spot for ST-601 was still    also visible. Second 2 hr TLC showed more product spot and    intermediate spot but no ST-601 spot.-   7. 30 mL of distilled water and 30 mL of saturated sodium chloride    solution were added to the reaction solution and stirred for 30    minutes.-   8. The reaction solution was concentrated to a volume of 65 mL    (vacuum of 14 mmHg was adequate on rotovap) and then extracted with    2×30 mL of toluene.-   9. The resultant extract was dried over anhydrous magnesium sulfate    and filtered.-   10. The filtrate was rotovaped to give 3.1 g crude ST-602 (MWt=194)    as a brown oil with no tarry nature.-   11. Labeled as ST-602-018 will be carried forward for cyclization    experiment

Example 23—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione ST-617 (Step 3)

Aim: Carry out Step 3 to study cyclization of much cleaner crude mixturefrom condensation.

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL Toluene into a        100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Heated to 100° C. while stirring    -   4. Added crude ST-602-019a solution (12.4 g solution in        toluene). Yellow-brown slurry.    -   5. Started stirring and heated to reflux (˜110° C.). Color        changed to reddish brown in 15 mins. Slow H₂S gas evolution was        observed which is passed through a caustic bubbler and no H₂S is        exited.    -   6. Continued reflux for 6 hours.    -   7. A sample was taken for HPLC (method ST-1). No starting        material present. Product ST-603 was present but also some other        small peaks.    -   8. The reaction was cooled to 25° C. (RT)    -   9. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   10. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. Weak exotherm was observed but        no H₂S gas smell at all.    -   11. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Very few insolubles are visible at the end        of the 3 hours.    -   12. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Much more easily filtered than        comparative ST-603-005.    -   13. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   14. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in solids    -   15. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol followed by 20 mL of cold        heptane.    -   16. Dried in vacuum oven to constant weight.    -   17. Weight of crude ST-603 crystalline powder is 874 mg (˜21%        yield) (Mol Wt=226) GC=97.3/a    -   18. Labelled as ST-603-020.

Example 24—Synthesis of crude4-methyl-5-pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 to study cyclization of much cleaner crude mixturefrom condensation using solvent system and slightly higher refluxtemperature from U.S. Pat. No. 7,288,652

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 25 mL toluene+30 mL        xylene into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirred.    -   3. Heated to 130° C. while stirring    -   4. Added crude ST-602-019b solution (˜10 mL in toluene).        Yellow-brown slurry.    -   5. Started stirring and heated to reflux (˜110° C.). Color        changed to reddish brown in 15 mins. Slow H₂S gas evolution is        observed which is passed through a caustic bubbler and no H₂S is        exited.    -   6. Continued reflux for 6 hours.    -   7. A sample was taken for HPLC (method ST-1). No starting        material present. Product ST-603 is present but also some other        small peaks.    -   8. The reaction was cooled to 25° C. (RT)    -   9. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   10. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. Weak exotherm was observed but        no H₂S gas smell at all.    -   11. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Very few insolubles are visible at the end        of the 3 hours.    -   12. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles, easy filtration may even work with        paper.    -   13. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   14. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in solids    -   15. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol followed by 20 mL of cold        heptane.    -   16. Dried in vacuum oven to constant weight.    -   17. Weight of crude ST-603 crystalline powder is 826 mg—very        similar and within error of the yield produced by the method of        the previous Example, so apparently the higher boiling point        does not materially affect to the reaction yield.    -   18. Labelled as ST-603-021.

Example 25—Synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2)

Aim: Replace base in Step 2 with 2× potassium t-butoxide, as describedin U.S. Pat. No. 7,288,652

Procedure

-   -   1. Added 4.1 g (0.0362 mole) of potassium t-butoxide powder        (MWt 112) powder and 25 mL of dry THF into a 100-mL 2-neck RBF        at 0° C. Stirred for 5 minutes    -   2. Added 2.9 g (0.0326 mole) of methyl propionate (Mwt 88) into        the flask using a dropping funnel over 15 minutes. Color turned        pale yellow.    -   3. Stirred for an additional 15 minutes at 0° C. No color        change.    -   4. 2.5 g (0.0181 mole) of ST-601 was dissolved in 10 mL of THF        and added into the reaction over 30 minutes while allowing the        reaction to come to RT (hr). No gas evolution or exotherm.    -   5. Stirred at RT for 6 hours. Monitored by TLC every 2 hours.    -   6. TLC shows ˜60% product (ST-602) spot (Rf 0.4) began forming        after 2 hrs at RT and an intermediate spot (Rf 0.2) and <10%        spot for ST-601 was still also visible. Second 2 hr TLC showed        more product spot and intermediate spot but no ST-601 spot.    -   7. 30 mL of distilled water and 30 mL of saturated sodium        chloride solution were added to the reaction solution and        stirred for 30 minutes.    -   8. The reaction solution was concentrated to a volume of 65 mL        (vacuum of 14 mmHg was adequate on rotovap) and then extracted        with 2×30 mL of toluene.    -   9. The resultant extract was dried over anhydrous magnesium        sulfate and filtered.    -   10. The filtrate was rotovaped to give 2.7 g crude ST-602        (MWt=194) as a brown oil with little tarry nature.    -   11. Labeled as ST-602-022 will be carried forward for        cyclization experiment as per U.S. Pat. No. 7,288,652 for total        yield comparisons.

Example 26—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Cary out Step 3 to study overall yield an purity of Steps 1, 2, and3 as described in U.S. Pat. No. 7,288,652

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 25 mL toluene+30 mL        xylene into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirred.    -   3. Heated to 130° C. while stirring    -   4. Added crude ST-602-019b solution (˜10 mL in toluene).        Yellow-brown slurry.    -   5. Started stirring and heated to reflux (˜110° C.). Color        changed to reddish brown in 15 mins. Slow H₂S gas evolution was        observed which is passed through a caustic bubbler and no H₂S is        exited.    -   6. Continued reflux for 6 hours.    -   7. A sample was taken for HPLC (method ST-1). No starting        material present. Product ST-603 was present but also some other        small peaks.    -   8. The reaction was cooled to 25° C. (RT)    -   9. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   10. To the above beaker was slowly added (over 10 min) the        content of the reaction flask. Weak exotherm was observed but no        H₂S gas smell at all.    -   11. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Very few insolubles are visible at the end        of the 3 hours.    -   12. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles, easy filtration may even work with        paper.    -   13. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   14. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in solids    -   15. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol followed by 20 mL of cold        heptane.    -   16. Dried in vacuum oven to constant weight.    -   17. Weight of crude ST-603 crystalline powder was 708 mg.        Labelled as ST-603-023. GC shows purity of 96.7%.

Example 27—Catalyzed synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione. ST-617 (Step 3)

Aim: Carry out Step 3 using tetrabutyl phosphonium chloride intoluene+water

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL Toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of tetrabutyl phosphonium chloride    -   4. Heated to 100° C. while stirring    -   5. Added crude ST-602-034a solution (12 g solution in toluene).        Yellow-Green slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to red-brown after 20 min. Some H₂S gas evolution was        observed which was passed through a caustic bubbler and no H₂S        was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. ˜50% starting material present.        Product ST-603 is also present but some other spots also        present.    -   9. Continued reflux for 2 hours.    -   10. A sample was taken for TLC. <5% starting material present.        Product ST-603 is also present but some other spots also        present.    -   11. The reaction was cooled to 25° C. (RT)    -   12. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   13. To the above beaker was slowly added (over 10 min) the        content of the reaction flask. No exotherm was observed and no        H₂S gas smell at all.    -   14. The resulting mixture was stirred for 2 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Some insolubles are visible at the end of        the 2 hours.    -   15. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   16. The organic layer was separated (both were colored        red-brown), dried over 2 g anhydrous sodium sulfate and        concentrated on a rotovap at <50° C. to 20 mL volume.    -   17. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in sticky solids only but        titutration with hexane did yield approx. 400 mg of flowable        red-brown powder. TLC shows mostly ST-603—sample saved as        ST-603-35.

Example 28—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene under reflux pressure

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene into a        200 mL SS316 autoclave under nitrogen.    -   2. Added crude ST-602-019d solution (˜10 mL in toluene).        Yellow-brown slurry.    -   3. Started stirring, sealed the autoclave, and heated to jacket        temperature 180° C.    -   4. Pressure gauge showed increasing pressure from 1 ATM to 16.4        ATM after 2 hours and held steady.    -   5. Continued 2 additional hours for a total of 4 hours.    -   6. Released the pressure into a caustic bubbler.    -   7. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   8. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. Weak exotherm was observed and        some H₂S gas could be detected by smell.    -   9. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Few insolubles were visible at the end of        the 3 hours.    -   10. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles.    -   11. The organic layer was separated (both layers were colored        red), dried over 2 g anhydrous sodium sulfate, and concentrated        on a rotovap at 550° C. to 20 mL volume.    -   12. The resulting slurry was diluted with 20 mL of methanol and        stirred at about 23° C. (room temperature or RT) for 2 h,        resulting in solids.    -   13. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol, followed by 20 mL of cold        heptane.    -   14. Dried in vacuum oven to constant weight.    -   15. Weight of crude ST-603 brown pasty powder is 943 mg. TLC        showed the product spot but many other smaller spots. Labelled        as ST-603-024. GC purity=64.3%.

Example 29—Synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2) Aim: Scale-upStep 2 Procedure

-   -   1. Add 32.8 g (0.2896 mole) of potassium t-butoxide powder and        160 mL of dry THF+40 mL 1,4-dioxane into a 500-mL 2-neck RBF at        0° C. Stirred for 5 minutes    -   2. Added 23.2 g (0.2608 mole) of methyl propionate into the        flask using a dropping funnel over 15 minutes. Color turned pale        yellow.    -   3. Stirred for an additional 15 minutes at 0° C. No color        change.    -   4. Added 20 g (0.1448 mole) of ST-601 dissolved in 40 mL of        THF+40 mL of 1,4-dioxane over 30 minutes while allowing the        reaction to come to RT. No gas evolution or exotherm was        observed.    -   5. Stirred at RT for 12 hours. Monitored by TLC every 2 hours.    -   6. 240 mL of distilled water and 240 mL of saturated sodium        chloride solution were added to the reaction solution, which was        subsequently stirred for 30 minutes.    -   7. The reaction solution was concentrated to a volume of 510 mL        (vacuum of 14 mmHg was adequate on rotovap) and then extracted        with 2×240 mL of toluene.    -   8. The resultant extract was rotovaped to give 97.7 g crude        ST-602 as a brown oil with no tarry nature.    -   9. The solution was divided into eight equal parts and labelled        as ST-602-25a, b, c, d, e f, g, h for comparative cyclization        experiments.

Example 30—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione ST-617 (Step 3)

Aim: Carry out Step 3 in toluene in autoclave under reflux

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene into a        200-mL SS316 autoclave under nitrogen.    -   2. Added crude ST-602-025a solution (˜10 mL in toluene).        Yellow-brown slurry.    -   3. Started stirring, sealed the autoclave, and heated to jacket        temperature 180° C.    -   4. Pressure gauge showed increasing pressure from 1 ATM to 16.1        ATM after 2 hours and held steady.    -   5. Released the pressure into a caustic bubbler.    -   6. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   7. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. A weak exotherm was observed and        some H₂S gas was detected.    -   8. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Few insolubles were visible at the end of        the 3 hours.    -   9. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles.    -   10. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   11. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h, resulting in solids    -   12. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol, followed by 20 mL of cold        heptane.    -   13. Dried in vacuum oven to constant weight.    -   14. Weight of crude ST-603 brown pasty powder was 802 mg. TLC        showed some product but also many less concentrated side        products. Labelled as ST-603-026.

Example 31—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene in autoclave under reflux for 12 h

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene into a        200-mL SS316 autoclave under nitrogen.    -   2. Added crude ST-602-025b solution (˜10 mL in toluene).        Yellow-brown slurry.    -   3. Started stirring, sealed the autoclave, and heated to jacket        temperature 180° C.    -   4. Pressure gauge showed increasing pressure from 1 ATM to 16.1        ATM after 2 hours and held steady.    -   5. Held under pressure overnight.    -   6. Released the pressure into a caustic bubbler.    -   7. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO dissolved in 30 mL water and 10 mL of THF at RT.    -   8. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. A weak exotherm was observed and        some H₂S gas was detected.    -   9. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Few insolubles were visible at the end of        the 3 hours.    -   10. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles.    -   11. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   12. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in solids.    -   13. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol followed by 20 mL of cold        heptane.    -   14. Dried in vacuum oven to constant weight.    -   15. Weight of crude ST-603 brown pasty powder was 985 mg. TLC        showed some product but many less concentrated side products        were also visible. Labelled as ST-603-027. GC purity=54%.

Example 32 Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in xylene in autoclave under reflux

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL xylene into a        200-mL SS316 autoclave under nitrogen.    -   2. Added crude ST-602-025c solution (˜10 mL in toluene).        Yellow-brown slurry.    -   3. Started stirring, sealed the autoclave and heated to jacket        temperature 180° C.    -   4. Pressure gauge showed increasing pressure from 1 ATM to 15.1        ATM after 2 hours and held steady.    -   5. Continued 2 additional hours for a total of 4 hours.    -   6. Released the pressure into a caustic bubbler.    -   7. In a 100-mL beaker was prepared a quenching mixture of 7 g of        solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   8. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. A weak exotherm was observed and        some H₂S gas was detected.    -   9. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Few insolubles were visible at the end of        the 3 hours.    -   10. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles.    -   11. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   12. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in solids.    -   13. The solids were collected by filtration, rinsed 2× with 20        mL of refrigerated cold methanol followed by 20 mL of cold        heptane.    -   14. Dried in vacuum oven to constant weight.    -   15. Weight of crude ST-603 brown pasty powder was 764 mg. TLC        showed some product but also many less concentrated side        products. Labelled as ST-603-028. GC purity=68%.

Example 33—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using anammonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of Aliquat 336        (N-methyl-N,N,N-trioctan-1-ammonium chloride).    -   4. Heated to 100° C. while stirring    -   5. Added crude ST-602-025d solution (12.4 g solution in        toluene). Yellow slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to reddish brown in 15 mins. Fast H₂S gas evolution was        observed; gas was passed through a caustic bubbler and no H₂S        was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. No starting material present.        Product ST-603 was present but also many other small peaks.    -   9. The reaction was cooled to 25° C.    -   10. In a 100-ml beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   11. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. A weak exotherm was observed but        no H₂S gas was detected.    -   12. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Very few insolubles were visible at the        end of the 3 hours.    -   13. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   14. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   15. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in sticky solids only—no clean        powder resulted, so reaction was discarded.

Example 34—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using anammonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S and 50 mL toluene+5 mL water        into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of benzalkonium chloride.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-025e solution (12.4 g solution in        toluene). Yellow slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to dark brown in 5 mins. Very fast H₂S gas evolution was        observed; the gas was passed through a caustic bubbler and no        H₂S was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. No starting material present.        Very little product ST-603 was present and lots of streaking was        visible on the TLC.    -   9. With the TLC showing poor conversion the reaction was        discarded.

Example 35 Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-61?(Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using anammonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of benzyltrimethylammonium tribromide.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-025f solution (12.4 g solution in        toluene). Brown slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changes to brown in 15 min. Moderate H₂S gas evolution was        observed; the gas was passed through a caustic bubbler and no        H₂S was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. No starting material present.        Product ST-603 was present but also many other compounds in        lower concentrations.    -   9. The reaction was cooled to 25° C.    -   10. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   11. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. A weak exotherm was observed but        no H2s gas was detected.    -   12. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Very few insolubles were visible at the        end of the 3 hours.    -   13. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   14. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   15. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in sticky solids only.    -   16. Titurated the sticky solids with a mixture of DMSO+water        until brown/red solid powder was formed on the side of the        beaker.    -   17. Collected the solids and checked by TLC, ST-603 was present        but still many other trailing spots.    -   18. Reaction was discarded.

Example 36—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using anammonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of tributylammonium acetate.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-025 g solution (12.4 g solution in        toluene). Greenish slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to greenish red-brown in 10 min. Some H₂S gas evolution        was observed; the gas was passed through a caustic bubbler and        no H₂S was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. Starting material present.        Product ST-603 was also present but a large streak was visible        at bottom of TLC.    -   9. Refluxed for 2 more hours.    -   10. A sample was taken for TLC. No more starting material        present. Product ST-603 was present with a small streak at        bottom of TLC    -   11. The reaction was cooled to 25° C.    -   12. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   13. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. A weak exotherm was observed but        no H₂S gas was detected.    -   14. The resulting mixture was stirred over 3 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Very few insolubles were visible at the        end of the 3 hours.    -   15. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. VERY slow filtration.    -   16. The organic layer was separated (both are colored red),        dried over 2 g anhydrous sodium sulfate, and concentrated on a        rotovap at <50° C. to 20 mL volume.    -   17. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in sticky solids only—no clean        powder resulted, so reaction was discarded.

Example 37 Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using anammonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of tetraethylammonium iodide.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-025 h solution (12.4 g solution in        toluene). Brown slurry.    -   6. Started stirring and heated to reflux (˜110° C.). No color        change after 20 mins. No H₂S gas evolution was observed.        Regardless, a caustic bubbler was used and no H₂S was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. Mostly starting material present.    -   9. Refluxed for 2 more hours.    -   10. A sample was taken for TLC. Still mostly starting material        present. Faint ST-603 spot was present with streaking at bottom        of TLC.    -   11. Refluxed overnight.    -   12. TLC showed little starting material remaining, but still        only a faint ST-603 spot.    -   13. Reaction was discarded.

Example 38—Synthesis of methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, ST-602 (Step 2) Aim: Scale-upStep 2 Procedure

-   -   1. Add 32.8 g (0.2896 mole) of potassium t-butoxide powder and        160 mL of dry THF+40 mL 1,4-dioxane into a 500-mL 2-neck RBF at        0° C. Stirred for 5 minutes.    -   2. Added 23.2 g (0.2608 mole) of methyl propionate into the        flask using a dropping funnel over 15 minutes. Color turned pale        yellow.    -   3. Stirred for an additional 15 minutes at 0° C. No color        change.    -   4. Add 20 g (0.1448 mole) of ST-601 was dissolved in 40 mL of        THF+40 mL of 1,4-dioxane and added into the reaction over 30        minutes while allowing the reaction to come to RT (˜hr). No gas        evolution or exotherm.    -   5. Stirred at RT for 12 hours. Monitored by TLC every 2 hours.    -   6. 240 mL of distilled water and 240 mL of saturated sodium        chloride solution were added to the reaction solution and        stirred for 30 minutes.    -   7. The reaction solution was concentrated to a volume of 510 mL        (vacuum of 14 mmHg was adequate on rotovap) and then extracted        with 2×240 mL of toluene.    -   8. The resultant extract was rotovaped to give 97.7 g crude        ST-602 as a brown oil with no tarry nature.    -   9. Divided the solution into eight equal parts and labelled as        ST-602-34a, b, c, d, e, f, g, h for comparative cyclization        experiments.

Example 39—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using aphosphonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of tetrabutyl phosphonium chloride.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-034a solution (12 g solution in toluene).        Yellow-green slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to red-brown after 20 min. Some H₂S gas evolution was        observed; gas was passed through a caustic bubbler and no H₂S        was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. ˜50% starting material present.        Product ST-603 was also present, in addition to some side        products.    -   9. Continued reflux for 2 hours.    -   10. A sample was taken for TLC. <5% starting material present.        Product ST-603 was present, in addition to some side products.    -   11. The reaction was cooled to 25° C.    -   12. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   13. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. No exotherm was observed and no        H₂S gas was detected.    -   14. The resulting mixture was stirred for 2 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Some insolubles were visible at the end of        the 2 hours.    -   15. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   16. The organic layer was separated (both are colored        red-brown), dried over 2 g anhydrous sodium sulfate, and        concentrated on a rotovap at <50° C. to 20 mL volume.    -   17. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in sticky solids, but        titutration with hexane yielded approximately 400 mg of flowable        red-brown powder. TLC showed mostly ST-603—sample saved as        ST-603-35.

Example 40—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using aphosphonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of methyltriphenoxyphosphonium iodide.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-034b solution (12 g solution in toluene).        Yellow slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to brown in 1 min. Some H₂S gas evolution was observed;        gas was passed through a caustic bubbler and no H₂S was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. No starting material present.        Product ST-603 was present but a large number of other compound        also present.    -   9. The reaction was cooled to 25° C.    -   10. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   11. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. No exotherm was observed and no        H₂S gas was detected.    -   12. The resulting mixture was stirred for 2 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Some insolubles were visible at the end of        the 2 hours.    -   13. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   14. The organic layer was separated (both are colored        red-brown), dried over 2 g anhydrous sodium sulfate, and        concentrated on a rotovap at <50° C. to 20 mL volume.    -   15. The resulting slurry was diluted with 20 ml of methanol and        stirred at RT for 2 h resulting in sticky solids—no clean powder        resulted so reaction was discarded.

Example 41—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using aphosphonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-ml 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of tetraphenyl phosphonium chloride.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-034c solution (12 g solution in toluene).        Yellow-green slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to red-brown after 5 min. Some H₂S gas evolution was        observed; gas was passed through a caustic bubbler and no H₂S        was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. ˜10% starting material present.        Product ST-603 was present, in addition to a number of side        products.    -   9. The reaction was cooled to 25° C.    -   10. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   11. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. No exotherm was observed and no        H₂S gas was detected.    -   12. The resulting mixture was stirred for 2 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Some insolubles were visible at the end of        the 2 hours.    -   13. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   14. The organic layer was separated (both are colored        red-brown), dried over 2 g anhydrous sodium sulfate, and        concentrated on a rotovap at <50° C. to 20 mL volume.    -   15. The resulting slurry was diluted with 20 ml of methanol and        stirred at RT for 2 h resulting in sticky solids. Tituration did        not yield any flowable powder product—so, reaction was        discarded.

Example 42—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene and water under reflux using aphosphonium salt as a phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene+5 mL        water into a 100-mL 2-neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 100 mg of trihexyltetradecylphosphonium chloride.    -   4. Heated to 100° C. while stirring    -   5. Added crude ST-602-034d solution (12 g solution in toluene).        Brown slurry.    -   6. Started stirring and heated to reflux (˜110° C.). No color        change after 20 mins. Some H₂S gas evolution was observed; gas        was passed through a caustic bubbler and no H₂S was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. No starting material present.        Very little product spot if at all and many side products        detected—so, reaction was discarded without work up.

Example 43—Synthesis of crude4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, ST-617 (Step 3)

Aim: Carry out Step 3 in toluene under reflux using an ammonium salt asa phase transfer catalyst

Procedure

-   -   1. Added 5.65 g (0.025 mole) of P₂S₅ and 50 mL toluene into a        100-ml 2 neck RBF under nitrogen.    -   2. Yellow slurry but easily stirrable.    -   3. Added 200 mg of Aliquat HTA-1.    -   4. Heated to 100° C. while stirring.    -   5. Added crude ST-602-034e solution (12 g solution in toluene).        Yellow slurry.    -   6. Started stirring and heated to reflux (˜110° C.). Color        changed to red-brown after 10 min. Some H₂S gas evolution was        observed; gas was passed through a caustic bubbler and no H₂S        was exited.    -   7. Continued reflux for 2 hours.    -   8. A sample was taken for TLC. <10% starting material present.        Product ST-603 was present but few other spots also present.    -   9. Continued reflux for 2 hours.    -   10. A sample was taken for TLC. <5% starting material present.        Product ST-603 was present but some other spots also present.    -   11. The reaction was cooled to 25° C.    -   12. In a 100-mL beaker was prepared a quenching mixture of 7 g        of solid Na₂CO₃ dissolved in 30 mL water and 10 mL of THF at RT.    -   13. To the above beaker was slowly added (over 10 min) the        contents of the reaction flask. Mild exotherm was observed but        no H₂S gas was detected.    -   14. The resulting mixture was stirred for 2 hours to complete        quench of the reaction (in a very high vent hood attached to a        scrubber for safety). Some insolubles were visible at the end of        the 2 hours.    -   15. The reaction slurry was passed through a 1″ celite bed to        remove the fine insolubles. Slow filtration.    -   16. The organic layer was separated (both are colored        red-brown), dried over 2 g anhydrous sodium sulfate, and        concentrated on a rotovap at <50° C. to 20 mL volume.    -   17. The resulting slurry was diluted with 20 mL of methanol and        stirred at RT for 2 h resulting in slightly sticky solids.        Titutration with hexane yielded 830 mg of flowable red-brown        powder. TLC showed mostly ST-603—sample saved as ST-603-39.

INCORPORATION BY REFERENCE

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims. The contents of allreferences, patents, and published patent applications, and patentapplications cited throughout this application are incorporated hereinby reference.

1-20. (canceled)
 21. A method of making a purified oltipraz composition,comprising the steps of: (i) reacting a quantity ofpyrazine-2-carboxylic acid methyl ester with methyl propionate to formmethyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, wherein the reactionis carried out in the presence of a base and a solvent comprising1,4-dioxane in tetrahydrofuran (THF), wherein the ratio of 1,4-dioxanein the THF is at least about 1:5; (ii) adding at least one aqueousliquid to quench the reaction in Step (i); (iii) adding a nonpolarorganic solvent and an ionic salt, thereby forming a compositioncomprising an aqueous component and an organic component, wherein theorganic component comprises the nonpolar solvent and methyl2-methyl-3-oxo-3-(pyrazin-2-yl) propanoate; (iv) separating the organiccomponent from the aqueous component; (v) reacting the methyl2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate ester in the organic componentwith P₂S₅ in the presence of a nonpolar organic solvent to form4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione (oltipraz); (vi)quenching the reaction with an aqueous composition to yield acomposition comprising (i) an aqueous component and (ii) an organiccomponent that comprises oltipraz; (vii) separating the organiccomponent comprising oltipraz to yield an organic composition comprisingoltipraz in the nonpolar organic solvent; (viii) reducing the amount ofsolvent in the organic composition; (ix) precipitating the oltipraz inthe organic composition to yield a composition comprising oltipraz; (x)separating the precipitated oltipraz; and (xi) purifying the separatedoltipraz precipitate.
 22. The method according to claim 21, wherein thestep of purifying comprises recrystallization.
 23. The method accordingto claim 21, wherein the step of purifying does not comprisechromatographic separation.
 24. The method according to claim 22,wherein the step of purifying comprises recrystallization and does notcomprise chromatographic separation.
 25. The method according to claim21, wherein step (viii) comprises evaporating at least a portion of thesolvent in the organic composition, step (ix) comprises adding to theorganic composition a solvent that causes the oltipraz to precipitate,and step (x) comprises separating the oltipraz by filtering.
 26. Themethod according to claim 21, wherein the reaction of step (i) iscarried out in the presence of a base comprising potassium t-butoxide orsodium pentanoate.
 27. The method according to claim 26, wherein thebase comprises potassium t-butoxide.
 28. The method according to claim26, wherein the mole ratio of the base to methyl propionate is fromabout 3:1 to about 1:1.
 29. The method according to claim 21, whereinthe ratio of 1,4-dioxane to THF in Step (i) is from about 1:5 to about1:3.
 30. The method according to claim 29, wherein the ratio of1,4-dioxane to THF in Step (i) is from about 1:4.
 31. The methodaccording to claim 21, wherein the nonpolar solvent in Step (iii) is thesame nonpolar solvent used in Step (v).
 32. The method according toclaim 31, wherein the nonpolar organic solvent used in Step (iii)comprises an aromatic solvent.
 33. The method according to claim 32,wherein the nonpolar organic solvent in Step (v) comprises toluene orxylene.
 34. The method according to claim 33, wherein the nonpolarsolvent in Step (iii) and Step (v) is toluene.
 35. The method accordingto claim 21, wherein the reaction of step (i) is carried out in thepresence of a base comprising potassium t-butoxide or sodium pentanoate,and the ratio of 1,4-dioxane to THF in Step (i) is from about 1:5 toabout 1:3.
 36. The method according to claim 35, wherein the mole ratioof the base to methyl propionate in step (i) is from about 3:1 to about1:1, and the ratio of 1,4-dioxane to THF in Step (i) is about 1:4. 37.The method according to claim 22, wherein the reaction of step (i) iscarried out in the presence of a base comprising potassium t-butoxide orsodium pentanoate, and the ratio of 1,4-dioxane to THF in Step (i) isfrom about 1:5 to about 1:3.
 38. The method according to claim 37,wherein the mole ratio of the base to methyl propionate in step (i) isfrom about 3:1 to about 1:1, and the ratio of 1,4-dioxane to THF in Step(i) is about 1:4.
 39. The method according to claim 23, wherein thereaction of step (i) is carried out in the presence of a base comprisingpotassium t-butoxide or sodium pentanoate, and the ratio of 1,4-dioxaneto THF in Step (i) is from about 1:5 to about 1:3.
 40. The methodaccording to claim 39, wherein the mole ratio of the base to methylpropionate in step (i) is from about 3:1 to about 1:1, and the ratio of1,4-dioxane to THF in Step (i) is about 1:4.